Urinary Tract Infection
Preamble
The urinary tract comprises the kidneys, ureters, bladder and urethra. The tract is expected to be normally sterile except for the distal part of the urethra, which has resident bacterial flora. The tract is normally protected from becoming infected by the flushing effect of urinary voiding and immunological mechanisms.
The inner lining of the bladder, the urothelium (which comprises transitional epithelia), has several important functions. It acts as a membrane that essentially prevents urinary constituents from being reabsorbed into the system. It serves to monitor continuously the stretch and temperature of the bladder and monitors for the presence of noxious stimuli, thus it may have a role also therefore in the host's defences against urinary tract inflammation and infections.
A urinary tract infection (UTI) occurs when a part of the urinary tract becomes excessively colonized, usually by bacteria. A UTI can be asymptomatic or can cause symptoms such as lower abdominal discomfort, pain when urinating (dysuria), urgency to pass urine and/or a desire to pass urine excessively frequently. UTIs can progress to serious illness and some can be life threatening.
A variety of bacteria can produce urinary tract infections amongst which are e.g. Escherichia coli (E. coli), Klebsiella spp, Proteus spp, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus, Mycoplasma sp. and Chlamydia sp. Fungi and parasites also can infect the urinary tract. Generally the most common infecting organism is the bacterium E. coli, which causes around 85% of these infections.
It has been suggested that some bacteria that enter the bladder can penetrate into the lining urothelial cells where they can take up residence for months and also can multiply within the cells. In addition, it is thought that uropathogenic E. coli (UPEC) have fimbriae that enable them to attach to and then penetrate into urothelial cells. By residing intracellularly they render themselves less vulnerable to attack by the host's immune system and also from treatments with antibiotics that are taken orally or delivered systemically e.g. by intramuscular or intravenous injection.
Urinary tract infections are common complications of a variety of pathological conditions and diseases associated with abnormalities of urinary tract structure or function such as may occur with trauma or diseases and damage within the central nervous system or conditions associated with compromise of the immune system. Bacteria can enter the urinary tract through the urethra or, much less commonly, through the bloodstream. Urinary tract infections are much more common in females than in males.
Catheterisation of the urinary bladder, a system used to assist voiding or for monitoring urinary output, is commonly complicated by biofilm formation and catheter-acquired lower urinary tract infections. Biofilm formation within the bladder is a common complication from the use of indwelling catheters.
Some bacteria that enter the bladder can form biofilms on catheters or on the urothelium that lines the bladder cavity. A biofilm can be defined as a microbial sessile community characterised by cells that are irreversibly attached to a substratum or interface or to each other, are embedded in a matrix of extracellular polymeric substances that they have produced and exhibit an altered phenotype with respect to growth rate and gene transcription.
Bacteria within biofilms in the urinary tract tend to be more resistant to antibiotics and host immune systems than free bacteria. Urinary tract biofilms can produce a uniquely challenging problem to clinicians in attempting to eradicate them, because the organisms that make up biofilms may produce urease, an enzyme that hydrolyses urea, to produce free ammonia that raises the pH in the urine. This, in turn, can enable precipitation of minerals such as calcium phosphate or magnesium ammonium phosphate that can then provide another nidus for bacterial colonisation and multiplication.
Epidemiology
Annually in the US, approximately 1.7 million patients acquire hospital-acquired infections (HoAI) and approximately 100,000 will die from these infections, making HoAIs a leading cause of disease and death in the US. Aside from the death toll, the economic burden on the healthcare system is substantial, with the annual direct cost of HoAIs to US Hospitals estimated to be between $28 and $33 billion. Annual direct costs of HoAIs worldwide in Europe, Japan and the developing nations are billions more. This is a worldwide problem that is getting worse with HoAI rates two to five times higher in the developing world; this enormous strain threatens to further compromise already scarce financial and medical resources among the most vulnerable populations.
Many HoAIs are linked to the use of medical devices such as endotracheal tubes, central venous catheters and urinary catheters, with nearly 40% of healthcare associated infections (HeAI) being UTIs, or an estimated 600,000 patients per year in the USA. Catheter associated urinary tract infections (CAUTIs) account for an estimated 90% of these infections.
UTIs are the most common nosocomial infection experienced by patients in United States hospitals and are responsible for significant morbidity and excess hospital costs. In contemporary hospital services, between 15-25% of hospitalized patients receive urinary catheters during their hospital stay. The most important risk factor for developing a catheter-associated UTI is their prolonged use; the urinary catheter provides a breeding ground for bacteria and the slime-like aggregations of bacteria that are biofilms, which are nearly impossible to kill with conventional antibiotics.
Clinical Challenges
Antibiotics are the current mainstay treatment for symptomatic UTIs, but their effectiveness can be limited and excessive use of antibiotics to treat UTIs may lead to increased antibiotic resistance in uropathogenic bacteria. This situation is likely to be exacerbated by a foreseeable rise in the number of elderly immunocompromised patients.
An antimicrobial agent without bactericidal or bacteriostatic properties, which are typical properties of antibiotics, that could facilitate the removal of bacteria within the urinary tract without provoking protective mutations in uropathogens with which they come into contact would be considered a useful advance in the prophylaxis and treatment of UTI.
In North America, cranberries, a source of tannins (e.g. proanthocyanidins), have long been considered to have medicinal properties, and cranberry juice has until fairly recently been recommended for prevention and treatment of UTIs. However, clinical studies have yet to provide evidence of therapeutic efficacy in the prevention or treatment of catheter-associated urinary tract infections of either consumption of cranberry juice or extracts packaged in other ways for consumption. In addition, a Cochrane Database Systematic Review update (Jepson R. G., Williams G. and Craig J. C. Cranberries for preventing urinary tract infections. Cochrane Database of Systematic Reviews 2012, 10, Art. No.: CD001321. DOI: 10.1002/14651858.CD001321.pub5) concluded that there is no evidence that oral consumption of cranberry juice decreases the number of symptomatic urinary tract infections in women. They go on to add that the large number of dropouts/withdrawals from some of the trials indicates that cranberry juice may not be acceptable over long periods of time. Furthermore, enteral consumption of proanthocyanidins can contribute to nephrolithiasis (kidney stones) progression and enhance anticoagulation effects of other drugs. It is amongst the objects of the present invention to attempt a solution to these problems.
Other Bladder Pathologies
The luminal surface of the transitional epithelia of the urothelium is normally coated in a dense layer of glycosaminoglycans (GAGs). GAGs are long unbranched highly anionic polysaccharides and are retained at the transitional epithelial surface largely via their covalent linkage to a core protein (forming proteoglycans). The GAG layer (also known as the mucous layer) is thought to be important for a range of functions such as promoting urothelial impermeability to bacterial adherence/invasion and shielding the transitional epithelia from irritants. Damage to the GAG layer (and/or the underlying epithelia) can give rise to or contribute to e.g. chronic cystitis, Overactive bladder (OAB), and urethritis, where e.g. damage leads to exposure of the epithelia to substances which cause inflammation and/or pain and/or urge symptoms. Damage caused by partial bladder obstruction can also lead to such symptoms. Other causes of epithelium/GAG-layer damage are varied and include e.g. UTI, trauma and radiotherapy.
Chronic cystitis includes painful bladder syndrome (PBS), also known as interstitial cystitis, irradiation cystitis (usually resulting from radiotherapy), ketamine cystitis, granulomatous cystitis, follicular cystitis, trigonitis (inflammation of the trigone, including urethrotrigonitis, where both the trigone and urethra are affected), or abscess-associated cystitis (where the abscess can arise from e.g. UTI, trauma (e.g. bladder stones, catheterisation) or neurogenic bladder.
Treatment options to date include intravesical administration of so-called GAG layer supplements, which are themselves GAGs (in particular for chronic cystitis and OAB), together with an anti-inflammatory and/or anaesthetic to help manage the symptoms, though outcomes remain moderate. For OAB, anti-muscarinic agents are also employed to help control urge symptoms.
Bladder Cancer
Bladder cancer is any cancer arising within the bladder, most commonly carcinoma (i.e. involving the urothelium). It is a common cancer giving rise to serious morbidity and mortality.
Superficial tumors can be removed via transurethral resection and/or immunotherapy using intravesical administration of Bacillus Calmette-Guérin (BCG), an attenuated live bovine tuberculosis bacillus, Mycobacterium bovis. Other intravesical treatments include Anthracyclines (e.g. doxorubicin, valrubicin) and Mitomycins (e.g. Mitomycin C), especially for BCG-refractory cases. However, success rates can be improved, thereby decreasing progression of bladder cancer to stages where extensive surgical intervention is usually required.